Age and body composition related-effects on the pharmacokinetic disposition of STEALTH liposomal CKD- 602 (S-CKD602) in patients with advanced solid tumors

Abstract

2528 Background: STEALTH liposomes (SL), which contain lipids conjugated to polyethylene glycol (PEG), prolong the circulation time of a drug in plasma, achieve high and extended drug exposure in tumor, and are eliminated via the reticuloendothelial system (RES). S- CKD602 is a SL formulation of CKD-602, a camptothecin analogue. CKD-602 released from S-CKD602 is eliminated by the kidney. There is significant interpatient variability in the pharmacokinetic (PK) disposition of S-CKD602. Thus, there is a need to identify factors associated with the PK variability. We hypothesize that older patients (pts) have a reduced capacity to eliminate SL agents due to age-related impairment of the RES and that body composition alters the disposition of SL. Methods: PK studies of S-CKD602 were performed in a phase I study of S-CKD602 at 0.1 to 2.5 mg/m2 IV q 21 d in pts with solid tumors. Concentrations of encapsulated (E), released (R), and sum total (E + R) CKD-602 in plasma and CKD-602 in urine were measured by LC-MS/MS. Area under the plasma concentration versus time curve (AUC) was calculated and normalized by dose (AUC/dose). The ratio of total body weight to ideal body weight (TBW/IBW) was calculated as a measure of body composition. Results: Mean ± SD S-CKD602 sum total AUC/dose in pts < 60 (n = 13) and = 60 (n = 17) years of age (yo) were 4.5 ± 5.0 and 11.2 ± 11.0 (μg/ml·h)/(mg/m2), respectively (P<0.05). Controlling for age, there was a statistically significant inverse relationship between TBW/IBW and S-CKD602 AUC/dose where low TBW/IBW was associated with high AUC/dose in both age groups (P<0.05). The cumulative amount of CKD-602 recovered in the urine was 2.2-fold higher in pts < 60 yo compared with = 60 yo. Conclusions: These data suggest that pts = 60 yo have a reduced clearance of S-CKD602 and reduced release of CKD-602 from S- CKD602 compared with pts < 60 yo. In addition, pts < 60 and = 60 yo with a lean body composition may have a reduced tissue distribution and an increased plasma exposure of S-CKD602. The clinical significance of these differences and the factors associated with them need to be evaluated for S-CKD602 and other liposomal and nanoparticle anticancer agents. No significant financial relationships to disclose.